Selecting P2Y12 Inhibitor Therapy Based on Clopidogrel Metabolism Lowers Cumulative Ischemic Events
06/06/2023
Introduction and methods
Background
As carriers of cytochrome P450 2C19 (CYP2C19) loss-of-function (LOF) alleles who are treated with clopidogrel exhibit less platelet inhibition, they are at higher risk of ischemic events after PCI [1]. The TAILOR-PCI (Tailored Antiplatelet Therapy Following PCI) trial was designed to test the benefit of a genetically guided strategy for selecting oral P2Yââ inhibitor therapy following PCI [2,3]. Although it showed a 34% reduction in time to first ischemic event, this result was not statistically significant (adjusted HR: 0.66; P=0.056) [3].
Aim of the study
In a prespecified analysis of the TAILOR-PCI trial, the authors evaluated the incidence of cumulative ischemic events (i.e., first and recurrent ischemic events) in post-PCI patients with coronary artery disease (CAD) who were treated with either oral P2Yââ inhibitors according to a genetically guided strategy or conventional clopidogrel therapy.
Methods
The TAILOR-PCI trial was a prospective, international, multicenter, open-label RCT in which 5302 patients with acute or stable CAD were randomized to genetically guided P2Yââ inhibitor selection or conventional clopidogrel therapy for 12 months post-PCI. In the genetically guided group, carriers of the CYP2C19*2 or CYP2C19*3 LOF allele were identified with point-of-care genetic testing. Subsequently, LOF carriers were prescribed ticagrelor and noncarriers received clopidogrel. For patients assigned to but unable to tolerate ticagrelor, prasugrel was the recommended replacement. All patients were genotyped â¥12 months post-PCI to confirm or assess LOF status.
The current analysis included 5276 patients, of whom 1849 were LOF carriers (903 assigned to genetically guided strategy and 946 to conventional therapy).
Outcomes
The primary endpoint was the cumulative incidence of ischemic events (CV death, MI, stroke, stent thrombosis, and severe recurrent ischemia) at 12 months. The secondary endpoint was the cumulative incidence of major and minor bleeding events based on TIMI (Thrombolysis In Myocardial Infarction) criteria at 12 months.
Main results
- Among LOF carriers, the cumulative incidence of ischemic events at 12 months (primary endpoint) was reduced in the genetically guided group compared with the conventional therapy group (4.5% vs. 7.0%; HR: 0.61; 95%CI: 0.41â0.89; P=0.011).
- There was no significant difference in the cumulative incidence of major and minor bleeding events between LOF carriers assigned to the genetically guided strategy and those receiving conventional therapy (2.1% vs. 1.6%; HR: 1.36; 95%CI: 0.67â2.76; P=0.39).
Conclusion
This prespecified analysis of the TAILOR-PCI trial among CYP2C19 LOF carriers with CAD who underwent PCI showed a statistically significant 39% reduction in cumulative ischemic events at 12 months in patients assigned to a genetically guided strategy for selecting oral P2Yââ inhibitor therapy compared with those receiving conventional clopidogrel therapy. There was no significant difference in the cumulative incidence of TIMI major and minor bleeding events between the treatment groups.
References
Show references
1. Mega JL, Simon T, Collet JP, et al. Reduced function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA. 2010;304(16):1821â1830. https://doi.org/10.1001/jama.2010.1543
2. Pereira NL, Rihal CS, So DYF, et al. Clopidogrel pharmacogenetics. Circ Cardiovasc Interv. 2019;12(4):e007811. https://doi.org/10.1161/CIRCINTERVENTIONS.119.007811
3. Pereira NL, Farkouh ME, So D, et al. Effect of genotype-guided oral P2Y12 inhibitor selection vs conventional clopidogrel therapy on ischemic outcomes after percutaneous coronary intervention: the TAILOR-PCI randomized clinical trial. JAMA. 2020;324(8):761â771. https://doi.org/10.1001/jama.2020.12443
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